Host defense to fungi is poorly understood. Evidence indicates that restricting the availability of iron mediates resistance against bacteria. Unsaturated transferrin is thought to be the active component of this mechanism. Restricting the availability of iron may also provide defense against fungi. Whether transferrin restricted iron availability mediates host defense and whether fungi have mechanisms for overcoming host defense requires study. This proposal consists of defining the iron requirements of representative non-invasive, superficially invasive and systemically invasive fungi to test the hypothesis that invasive potential correlates inversely with the quantitative need for iron and directly with mechanisms to obtain iron. The fungal iron requirement will be determined and the capacity to utilize in vivo derived sources of iron will be compared. Experiments will be conducted in vitro with the aid of a radiometric fungal growth assay and chelated nutrient broth. Fungal surface chelating activity will be examined as an effective mechanism to obtain iron. A fungal mutant with a low iron requirement will be isolated and tested for increased invasive activity. Transferrin mediated host defense will be studied in vitro and in vivo using the guinea pig. The direct effect of transferrin on fungal invasion will be determined by monitoring the depth of penetration of Trichophyton mentagrophytes into a guinea pig skin explant in the presence of iron unsaturated and saturated transferrin. Guinea pigs will be iron saturated and infected at three anatomical levels with T. mentagrophytes. Morbidity, mortality and invasiveness will be monitored. The effect of immunization on pathogenicity and invasiveness will be tested in iron saturated animals. An antitransferrin antiserum will be developed and tested for its capacity to specifically inactivate or delete transferrin from guinea pigs. Treatment of iron saturated guinea pigs with apo-transferrin will be used to confirm the host defense value of transferrin against T. mentagrophytes and Rhizopus oryzae. Augmentation of host defense with chelators will be attempted.